Type II transmembrane domain hydrophobicity dictates the cotranslational dependence for inversion.
Bottom Line: Membrane insertion by the Sec61 translocon in the endoplasmic reticulum (ER) is highly dependent on hydrophobicity.Overall the cotranslational inversion of marginally hydrophobic NA TMDs initiates once ~70 amino acids past the TMD are synthesized, and the efficiency reaches 50% by ~100 amino acids, consistent with the positioning of this TMD class in type II human membrane proteins.Inversion of the M2 TMD, achieved by elongating its C-terminus, underscores the contribution of cotranslational synthesis to TMD inversion.
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Mentions: The analysis of protein sequence homology, property, and structural conservation has proved extremely useful in identifying protein topology and localization, functional domains, and the existence of certain cellular machinery (von Heijne, 2006; Daniels et al., 2010). However, the limited number of homologous sequences for human single-spanning membrane protein has hindered these approaches. Therefore we used the extensive human influenza A virus (IAV) sequence database to perform a comparative analysis of the TMD characteristics from natural single-spanning membrane proteins with Nout-Cin (HA and M2) and Nin-Cout (NA) orientations (Figure 1A).